Synthesis of Imidazopyridines from the Morita–Baylis–Hillman Acetates of Nitroalkenes and Convenient Access to Alpidem and Zolpidem

Abstract

A variety of functionalized imidazo[1,2-a]pyridines have been synthesized through a one-pot, room temperature, and reagent-free reaction between MBH acetates of nitroalkenes and 2-aminopyridines. The reaction involves a cascade inter-intramolecular double aza-Michael addition of 2-aminopyridines to MBH acetates. Our methodology is marked by excellent yield, regioselectivity and, above all, adaptability to synthesize imidazopyridine-based drug molecules such as Alpidem and Zolpidem.

A novel formulation of zolpidem for direct nose-to-brain delivery: synthesis, encapsulation and intranasal administration to mice

“…Yellow solid, mp 85–99°C; R f = 0.20 (petroleum ether – EtOAc, 3 : 1). The spectral data and melting point matched that reported by Namboothiri and coworkers . 1 H NMR (300 MHz, CDCl 3 ): δ 7.90 (s, 1H), 7.74 (d, J = 8.07 Hz, 2H), 7.62 (d, J = 8.80 Hz, 1H), 7.29 (d, J = 8.07 Hz, 2H), 7.11 (d, J = 8.80, 1H), 4.24 (q, J = 7.39 Hz, 2H), 4.02 (s, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 1.29 (t, J = 7.39 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ): δ 169.6 (CO), 144.5 (C), 144.0 (C), 137.6 (C), 131.4 (C), 129.4 (2 × CH), 128.4 (2 × CH), 127.6 (CH), 122.0 (C), 121.4 (CH), 116.8 (CH), 112.4 (C), 61.5 (CH 2 ), 30.9 (CH 2 ), 21.3 (CH 3 ), 18.4 (CH 3 ), 14.2 (CH 3 ); IR (KBr) 3429 (w), 1722 (s), 1185 (w), 789 (w) cm −1 ; MS (ESI) 308 [M] + .…”

“…White solid, mp 220–223°C; R f = 0.42 (CH 2 Cl 2 – MeOH, 4 : 1). The spectral data and melting point matched that reported by Namboothiri and coworkers . 1 H NMR (300 MHz, DMSO‐d6): δ 8.14 (s, 1H, Py), 7.69 (d, J = 8.06 Hz, 2H), 7.46 (d, J = 8.80 Hz, 1H, Py), 7.24 (d, J = 8.07 Hz, 2H), 7.10 (d, J = 8.80, 1H, Py), 2.33 (s, 3H), 2.28 (s, 3H); 13 C NMR (75 MHz, DMSO‐d6): δ 171.6 (CO), 142.8 (C), 141.9 (C), 136.5 (C), 132.0 (C), 129.1 (2 × CH), 127.8 (2 × CH), 127.1 (CH), 122.4 (C), 120.8 (CH), 116.5 (C), 115.9 (CH), 31.9 (CH 2 ), 20.9 (CH 3 ), 17.9 (CH 3 ); MS (ESI) 280 [M] + .…”

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

“…However, more recently these structures have been superseded by species incorporating different heterocyclic scaffolds such as zolpidem ( 6.45 ) [6,132–134], zaleplon ( 6.46 ) [135] and eszopiclone ( 6.47 ) [7]. These structures display anxiolytic effects but induce relatively little sedation [136].…”

Recent synthetic scenario on imidazo[1,2-a]pyridines chemical intermediate

“…Reaction of 2-aminpyridines 1.23 with 1.73 in the presence of catalytic amount of FeCl 2 provided 3-methylimidazo[1,2-a]pyridines 1.74 (Scheme 15). Recently, Namboothiri and his co-workers developed a mild and reagent-free one-pot synthesis route for synthesis of imidazo[1,2-a] pyridines 1.76 from 2-aminopyridines 1.23 and Morita-Baylis-Hillman (MBH) acetates 1.75 [48]. Scheme [49], ammonium chloride [50], montmorillonite clay K10 [51], bromo dimethyl sulfonium bromide (BDMS) (Scheme 16) [52].…”